It is well known that strains of herpes simplex virus (HSV) vary remarkably in their capacity to induce corneal disease, and recent work indicates that the attenuation or virulence of any given strain relates, at least in part, to its genetic makeup. Advances in biotechnology now make it possible to design studies to analyze the molecular basis for HSV virulence. The specific goal of this proposal is to identify the gene responsible for the variation in HSV strain sensitivity to interferon (IFN) alpha/beta and probe its function. Recent studies in our laboratory have established that HSV-1 strain 35 is approximately 100 times more sensitive than HSV-2(186) to the inhibitory effect of IFN alpha/beta. We have further found that IFN sensitivity correlates with HSV strain ocular virulence, i.e., IFN sensitive strains are less virulent in vivo than IFN resistant strains. We have also succeeded in isolating an IFN resistant intertypic recombinant (HSV-R4) whose parents are HSV-1(35) and HSV-2(186). We propose to use these three viruses to investigate the molecular basis for IFN sensitivity. Specifically we will: 1. map the genomic location of the gene responsible for differences in HSV strain sensitivity to IFN alpha/beta marker rescue; 2. determine the effect of IFN alpha/beta on the expression of immediate early gene alphaO in cells infected by IFN sensitive HSV-1(35), IFN resistant HSV-2(186), and IFN resistant intertypic recombinant HSV-R4; and 3. determine the nucleotide sequences of the gene responsible for the IFN sensitivity of HSV-1(35) and compare the sequence with that found in IFN resistant HSV-2(186). It is anticipated that the information acquired will provide greater insights into why HSV strains differ in virulence and perhaps suggest new strategies for combating HSV ocular infection.